title: Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons.
abstract: OBJECTIVE
  An APOC3 promoter haplotype has been previously associated with type 1 diabetes. In this population-based study, we investigated whether APOC3 polymorphisms increase type 2 diabetes risk and need for insulin treatment in lean participants.
  
  
  METHODS
  In the Rotterdam Study, a population-based prospective cohort (n = 7,983), Cox and logistic regression models were used to analyse the associations and interactive effects of APOC3 promoter variants (-482C > T, -455T > C) and BMI on type 2 diabetes risk and insulin treatment. Analyses were followed by replication in an independent case-control sample (1,817 cases, 2,292 controls) and meta-analysis.
  
  
  RESULTS
  In lean participants, the -482T allele was associated with increased risk of prevalent and incident type 2 diabetes: OR -482CT 1.47 (95% CI 1.13-1.92), -482TT 1.40 (95% CI 0.83-2.35), p = 0.009 for trend; HR -482CT 1.35 (95% CI 0.96-1.89), -482TT 1.68 (95% CI 0.91-3.1), p = 0.03 for trend, respectively. These results were confirmed by replication. Meta-analysis was highly significant (-482T meta-analysis p = 1.1 × 10(-4)). A borderline significant interaction was observed for insulin use among participants with type 2 diabetes (-482CT*BMI p = 0.06, -455TC*BMI p = 0.02).
  
  
  CONCLUSIONS
  At a population-based level, the influence of APOC3 promoter variants on type 2 diabetes risk varies with the level of adiposity. Lean carriers of the -482T allele had increased type 2 diabetes risk, while such an effect was not observed in overweight participants. Conversely, in overweight participants the -455C allele seemed protective against type 2 diabetes. The interaction of the variants with need for insulin treatment may indicate beta cell involvement in lean participants. Our findings suggest overlap in the genetic backgrounds of type 1 diabetes and type 2 diabetes in lean patients.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Hoek
authors.forename: T W
authors.initials: TW
authors.lastname: van Herpt
authors.forename: A
authors.initials: A
authors.lastname: Dehghan
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: A G
authors.initials: AG
authors.lastname: Lieverse
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: J C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: E J G
authors.initials: EJ
authors.lastname: Sijbrands
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D053305:Apolipoprotein C-III / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors; D013851:Thinness / Q000503:physiopathology*
chemical_list: D053305:Apolipoprotein C-III; D007004:Hypoglycemic Agents; D007328:Insulin